The underlying biological causes of neuropsychiatric disorders like schizophrenia, Alzheimer’s disease and major depressive disorder are very poorly understood. The majority of people with these mental health conditions are still diagnosed based on symptoms alone because there is a lack of objective and easy-to-measure biological signs of the illness. A good point of comparison is diabetes: the symptoms are caused by high levels of sugar in the blood. Measuring this parameter, therefore, gives doctors a solid clue to help them make a diagnosis.
Many neuropsychiatric diseases share the same outward symptoms, but the difficulty in finding a medicine that works leads to the conclusion that the biological causes could be very different. The big question is: are different processes being affected but producing the same symptoms? Or is it that the exact same processes are being disturbed in some way, but for whatever reason, they are presenting in different patients completely differently? This lack of clarity has caused a dramatic slowdown in new drugs being brought to the market. Mental illnesses like those mentioned have for decades been treated with the same list of 100 or so compounds in an empirical manner i.e. keep going until you find something that works.
The symptom in question – social dysfunction
The project partners in PRISM made progress in untangling the ways in which these diseases overlap, by trying to understand and classify them in a quantitative, biological way. They chose to focus on the symptom of social dysfunction, one of the earliest outward signs that can be observed in Alzheimer’s, schizophrenia and major depression. It is also considered an early indicator of cognitive deficits. PRISM probed the biological brain systems of traditionally-diagnosed schizophrenic and dementia patients using a wide range of state-of-the-art technologies and then analysed the data blind i.e. without information on the diagnosis, to see if the patients can be clustered into groups based on the underlying impaired brain biology.
Clustering into new groups
165 individuals with schizophrenia or Alzheimer’s disease, as well as a group of healthy controls, underwent a battery of tests. Of 4,330 biological markers picked up from functional magnetic resonance imaging (fMRI) scans (which register blood flow to functioning areas of the brain) and EEG tests (electroencephalograms, which show abnormalities in brain wave activity) along with observations of the participants’ behaviour, 139 markers showed a significant relationship with one of the two diseases, or with the control. More endpoints - 183 in total - showed a significant relationship with measures of social functioning. These new clusters were shown not to equate to existing diagnostic-based categorisation of patients.
The project also carried out genetic testing that revealed 604 genome-wide variants in 19 different places in the chromosome that have an association with social functioning. Further tests using preclinical models, by mirroring the tests carried out on human subjects, now allows the consortium to effectively back-translate the human clinical findings thereby expanding their neurobiological knowledge. This will be done as part of the PRISM 2 project.
Real-world social functioning measurement tools
New technologies played a major role in the PRISM project. Innovative statistical techniques derived insights from the data generated by genetic testing and neuroimaging, which was then consolidated with a wealth of existing clinical data from major European and global disease cohorts. PRISM also created new digital tools that can be used to measure social functioning linked to the neurobiological parameters, going further than the traditional diagnostic classification.
By passively measuring the number of phone calls and chats, location data from GPS signals (indicating outside visits and the length of time spent at home) generated by the participants’ smartphones, they were able to produce new and objective insights into the real-world environment and of a person’s individual social communication and exploration behaviour. This real-world analysis revealed three clusters that did not completely match the initial diagnostic groups, demonstrating the potential for further new classifications.
The smartphone-based behavioural endpoints developed by the project for measuring social functioning were shown to have potentially wide application in future research. PRISM initiated a dialogue with the Innovation Task Force of the European Medicines Agency with respect to the qualification of potential digital biomarkers for social functioning. The EMA Innovation Task Force provided encouraging feedback and progress is being made toward establishing the app outcomes as qualified biomarkers.
PRISM was able to accelerate the discovery and development of new treatments for neuropsychiatric conditions like schizophrenia and Alzheimer’s disease by differentiating these diseases based on the underlying impaired brain biology and showing where they overlap. They have bridged and important translation gap between discovery and validation of biomarkers and the technology that can measure them. They established a network of pre-clinical research sites that can perform high-quality studies, helping pave the way for recognition of social dysfunction as a registrable symptom across disorders. They also offered a new framework to help physicians better inform their patients of the complexity of their illness, leading to better understanding and disease management.
Their work continues to encourage the clinical community to consider neuropsychiatric disorders through a more quantitative lens, influencing patients, carers and the public, and adding to the growing evidence that neuropsychiatric disorders are ‘real’ and that there is demonstrable biomedical proof of their existence, just like physical illnesses. This is helping to reduce the stigma associated with mental disorders. The outline of the work carried out by PRISM was published in a special issue of Neuroscience & Biobehavioral Reviews on the PRISM project.
Funding for the follow-on phase of the PRISM project was granted in 2021. This new funding will allow the project to build on the work of PRISM by replicating their initial clinical findings on new patient cohorts and investigating the neurobiological mechanisms underlying these patient clusters. Major Depressive Disorders will be included as a third indication in the PRISM 2 project.